Oncogene-mechanics axis: KRAS G12C confers agility enabling malignant mechano-responses to peristalsis in colorectal cancer
- 1Department of Biomedical Engineering, Texas A&M University
Abstract
Oncogene activity and mechanical forces individually and collectively drive colorectal cancer, yet the integration of these signals is unknown. We used a patented peristalsis bioreactor to determine how oncogenic KRAS G12C mutations alter the cellular response to colonic peristalsis. Although both healthy intestinal cells (HIEC-6) and KRAS G12C cancer cells (SW837) sensed peristalsis via ERK phosphorylation (1.7-4.7X increase), their mechano-responses diverged significantly. Peristalsis triggered a 9-fold enrichment of LGR5+ cancer stem cells in KRAS G12C cancer cells, an effect absent in healthy HIEC-6 controls. Using Brillouin microscopy, we discovered that KRAS G12C possessed a mechanically primed state exhibiting 9% reduction in Brillouin Full Width at Half Maximum, indicative of lower intracellular viscosity. Peristalsis further decreased intracellular viscosity in KRAS G12C cells by 11.9%, accompanied by pronounced cell elongation, whereas HIEC-6 maintained viscoelastic homeostasis. This KRAS-dependent mechanical agility enabled KRAS G12C cancer cells to leverage, rather than resist peristalsis, resulting in LGR5 enrichment and malignant progression. Pharmacologic KRAS G12C inhibition with sotorasib reduced LGR5+ cells by 50% under peristalsis, reversing the malignant mechanotype. Conversely, introducing KRAS G12C into HIEC-6 disrupted their mechanical homeostasis and significantly increased LGR5, recapitulating the KRAS-dependent mechano-phenotype. Our findings identify a novel KRAS oncogene-mechanics axis, suggesting that targeting the cell’s mechanical state could be a powerful complement to emerging KRAS-directed therapies.
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BibTeX
@article{lamichhane2026oncogenemechanics,
title = {{Oncogene-mechanics axis: KRAS G12C confers agility enabling malignant mechano-responses to peristalsis in colorectal cancer}},
author = {Astha Lamichhane and Vsevolod Cheburkanov and Mykyta Kizilov and Abhinav Shenoy and Audrey G. Head and Vladislav Yakovlev and Shreya A. Raghavan},
journal = {Scientific Reports},
year = {2026},
month = sep,
doi = {10.1038/s41598-026-68015-6},
url = {https://doi.org/10.1038/s41598-026-68015-6},
note = {CC BY},
}
RIS
TY - JOUR
TI - Oncogene-mechanics axis: KRAS G12C confers agility enabling malignant mechano-responses to peristalsis in colorectal cancer
AU - Astha Lamichhane
AU - Vsevolod Cheburkanov
AU - Mykyta Kizilov
AU - Abhinav Shenoy
AU - Audrey G. Head
AU - Vladislav Yakovlev
AU - Shreya A. Raghavan
PY - 2026
DA - 2026/09/01
JO - Scientific Reports
DO - 10.1038/s41598-026-68015-6
UR - https://doi.org/10.1038/s41598-026-68015-6
AB - Oncogene activity and mechanical forces individually and collectively drive colorectal cancer, yet the integration of these signals is unknown. We used a patented peristalsis bioreactor to determine how oncogenic KRAS G12C mutations alter the cellular response to colonic peristalsis. Although both healthy intestinal cells (HIEC-6) and KRAS G12C cancer cells (SW837) sensed peristalsis via ERK phosphorylation (1.7-4.7X increase), their mechano-responses diverged significantly. Peristalsis triggered a 9-fold enrichment of LGR5+ cancer stem cells in KRAS G12C cancer cells, an effect absent in healthy HIEC-6 controls. Using Brillouin microscopy, we discovered that KRAS G12C possessed a mechanically primed state exhibiting 9% reduction in Brillouin Full Width at Half Maximum, indicative of lower intracellular viscosity. Peristalsis further decreased intracellular viscosity in KRAS G12C cells by 11.9%, accompanied by pronounced cell elongation, whereas HIEC-6 maintained viscoelastic homeostasis. This KRAS-dependent mechanical agility enabled KRAS G12C cancer cells to leverage, rather than resist peristalsis, resulting in LGR5 enrichment and malignant progression. Pharmacologic KRAS G12C inhibition with sotorasib reduced LGR5+ cells by 50% under peristalsis, reversing the malignant mechanotype. Conversely, introducing KRAS G12C into HIEC-6 disrupted their mechanical homeostasis and significantly increased LGR5, recapitulating the KRAS-dependent mechano-phenotype. Our findings identify a novel KRAS oncogene-mechanics axis, suggesting that targeting the cell’s mechanical state could be a powerful complement to emerging KRAS-directed therapies.
SN - 2045-2322
ER -